The emerging bacterial resistance to antibiotics is a major problem for public health. See, Ginzburg, E.; Namias, N.; Brown, M.; Ball, S.; Hameed, S. M.; Cohn, S. M. Int. J. Antimicrob. Agents, 2000, 16 (Suppl.), S39-S42; Chopra, I. J.; Hodgson, B. M.; Poste, G. Antimicrob. Agents Chemother., 1997, 41, 497-503. Increasing rate of infections caused by drug-resistant Gram positive and Gram negative bacteria demands accelerated research and development of new antibiotics. As an example, Daptomycin which is a thirteen-amino acid cyclic lipopeptide antibiotic (Huber et al., U.S. Pat. No. 4,885,243) is used in the treatment of systemic and life-threatening infections caused by Gram-positive organisms. See, Kline, M., Mason, E., Jr., Kaplan S., Lamberth, L., and Johnson, G., Comparative in-vitro activity of LY146032 and eight other antibiotics against Gram-positive bacteria isolated from children, Journal of Antimicrobial Chemotherapy, 1987, 20, 203-207; Steenbergen, J.; J. Alder, J.; Thorne, G. and Tally, F.; Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections, Journal of Antimicrobial Chemotherapy, 2005, 55, 283-288. It is particularly used in adults in the United States for skin and skin structure infections caused by Gram-positive bacteria Staphylococcus aureus, left-sided S. aureus endocarditis, osteomyelitis, prosthetic infections, and enterococcus infections. See, Fowler, G.; Boucher, H.; Corey, G.; Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus, N Engl J Med. 2006, 355 (7), 653-65; Davis, S.; McKinnon, P.; Hall, L.; Pharmacotherapy. 2007, 27 (12), 1611-1618; Steenbergen, J.; J. Alder, J.; Thorne, G. and Tally, F.; Daptomycin: a lipopeptide antibiotic for the treatment of serious Gram-positive infections, Journal of Antimicrobial Chemotherapy, 2005, 55, 283-288. Daptomycin is a natural product isolated from the broths of Streptomyces roseosporus. See, Debono, M.; Abbott, B. J.; Molloy, M; & et al.; Enzymatic and chemical modifications of lipopeptide antibiotic A21978C: the synthesis and evaluation of daptomycin (LY146032). J Antibiotics, 1988, 41, 1093-1105; Miao V.; Coëffet-Legal F.; Brian P.; Daptomycin biosynthesis in Streptomyces roseosporus: cloning and analysis of the gene cluster and revision of peptide stereochemistry, Microbiology (Reading, Engl.), 2005, 151 (Pt 5), 1507-23. Studies demonstrate that this compound disrupts multiple aspects of bacterial cell membrane function and therefore is effective in treating infections caused by multiple drug-resistant bacteria. See, Pogliano J; Pogliano, N; Silverman, J.; Daptomycin-Mediated Reorganization of Membrane Architecture Causes Mislocalization of Essential Cell Division Proteins, Journal of Bacteriology, 2012, 194 (17), 4494-4504; Baltz R.; Daptomycin: mechanisms of action and resistance, and biosynthetic engineering, Current Opinion in Chemical Biology, 2009, 13 (2), 144-151. However, the in vitro activity of daptomycin against Eterococci, including vancomycin-resistent Eterococci (VRE) is moderate and therefore its use in treatment of infections caused by VRE, without combining with other antibiotics, is limited. See, Moise; P A; Sakoulas G; McKinnell J A; Lamp K C; DePestel D D; Yoon M J; Reyes K; Zervos M J; Clinical Outcomes of Daptomycin for Vancomycin-resistant Enterococcus Bacteremia, Clin. Ther., 2015 Jul. 1, 37(7), 1443-1453. In recent years, daptomycin-resistance in Enterococci, particularly in vancomycin-resistant E. faecium and E. farcalis, has been increasingly reported in the United States, Europe, and Asia. See, Cleveland, K.; Gelfand, M.; Daptomycin-Nonsusceptible Enterococcal Infections, Infect Dis Clin Pract, 2013, 21, 79-84.
There is an urgent need for new antibiotic agents that are efficacious against microorganisms including those resistant to vancomycin, penicillin and methicillin.